Project summary Genome structure, at a fundamental level, can be described by the division of the genome into autosomes and sex chromosomes. Meiotic drive, segregation mechanisms, sexual antagonism, epistasis, benefits of higher or lower recombination, and drift have all been implicated in changes in chromosome number as well as the proportion of the genome contained within sex chromosomes. However, despite over a century of work, none of these factors can adequately explain the striking variation in genome organization across species. The long-term goals of our research program are: (1) to develop new and robust models to better explain the forces that lead to changes in the number of chromosomes and the proportion of the genome contained in sex chromosomes, and (2) to understand how these characteristics impact the evolution of other traits including common chromosomal disorders like Klinefelter syndrome and Turner syndrome. This will be achieved by implementing a three-pronged approach combining comparative, genomic, and theoretical methods to gain new insight into genome evolution. First, comparative phylogenetic methods will be applied to genomic and phenotypic data spanning long evolutionary time scales to estimate the rates of evolution of sex chromosomes and chromosome number and link variation in these rates with life-history or other traits. Over shorter time periods genetic and genomic studies are used within and among species to understand the nature of segregating variation in genome structure and genetic variation that is sexually antagonistic. Finally, these approaches are supplemented with theoretical work to test and develop hypotheses inspired by results or to aid in experimental design for genetic and genomic studies. Together, the results of this work will be an unprecedented understanding of the evolutionary forces that have shaped the large-scale structure of genome across the tree of life and continue to impact our genomes today